Anandappa Gayathri, Lampis Andrea, Cunningham David, Khan Khurum H, Kouvelakis Kyriakos, Vlachogiannis Georgios, Hedayat Somaieh, Tunariu Nina, Rao Sheela, Watkins David, Starling Naureen, Braconi Chiara, Darvish-Damavandi Mahnaz, Lote Hazel, Thomas Janet, Peckitt Clare, Kalaitzaki Ria, Khan Nasir, Fotiadis Nicos, Rugge Massimo, Begum Ruwaida, Rana Isma, Bryant Annette, Hahne Jens C, Chau Ian, Fassan Matteo, Valeri Nicola
Department of Medicine, The Royal Marsden NHS Trust, London and Sutton, United Kingdom.
Division of Molecular Pathology, The Institute of Cancer Research, London and Sutton, United Kingdom.
Clin Cancer Res. 2019 Jul 1;25(13):3830-3838. doi: 10.1158/1078-0432.CCR-18-3769. Epub 2019 Apr 5.
Anti-EGFR mAbs are effective in the treatment of metastatic colorectal cancer (mCRC) patients. status and tumor location (sidedness) are predictive markers of patients' response to anti-EGFR mAbs. Recently, low miR-31-3p expression levels have been correlated with clinical benefit from the anti-EGFR mAb cetuximab. Here, we aimed to validate the predictive power of miR-31-3p in a prospective cohort of chemorefractory mCRC patients treated with single-agent anti-EGFR mAbs.
miR-31-3p was tested by hybridization (ISH) in 91 pretreatment core biopsies from metastatic deposits of 45 patients with mCRC. Sequential tissue biopsies obtained before treatment, at the time of partial response, and at disease progression were tested to monitor changes in miR-31-3p expression overtreatment. miR-31-3p expression, sidedness, and status in pretreatment cell-free DNA were combined in multivariable regression models to assess the predictive value of each variable alone or in combination.
Patients with low miR-31-3p expression in pretreatment biopsies showed better overall response rate, as well as better progression-free survival and overall survival, compared to those with high miR-31-3p expression. The prognostic effect of miR-31-3p was independent from age, gender, and sidedness. No significant changes in the expression of miR-31-3p were observed when sequential tissue biopsies were tested in long-term or poor responders to anti-EGFR mAbs. miR-31-3p scores were similar when pretreatment biopsies were compared with treatment-naïve archival tissues (often primary colorectal cancer).
Our study validates the role of miR-31-3p as potential predictive biomarker of selection for anti-EGFR mAbs.
抗表皮生长因子受体（EGFR）单克隆抗体在转移性结直肠癌（mCRC）患者的治疗中有效。RAS状态和肿瘤位置（左右侧性）是患者对抗EGFR单克隆抗体反应的预测标志物。最近，低水平的miR-31-3p表达与抗EGFR单克隆抗体西妥昔单抗的临床获益相关。在此，我们旨在在前瞻性队列中验证miR-31-3p对接受单药抗EGFR单克隆抗体治疗的化疗难治性mCRC患者的预测能力。
通过原位杂交（ISH）在45例mCRC患者转移性病灶的91份治疗前核心活检组织中检测miR-31-3p。对治疗前、部分缓解时和疾病进展时获得的连续组织活检进行检测，以监测miR-31-3p表达在过度治疗中的变化。将治疗前无细胞DNA中的miR-31-3p表达、左右侧性和RAS状态纳入多变量回归模型，以评估每个变量单独或联合的预测价值。
与miR-31-3p高表达患者相比，治疗前活检中miR-31-3p低表达患者的总缓解率更高，无进展生存期和总生存期也更好。miR-31-3p的预后作用独立于年龄、性别和左右侧性。在长期或对抗EGFR单克隆抗体反应不佳的患者中进行连续组织活检检测时，未观察到miR-31-3p表达有显著变化。将治疗前活检与未经治疗的存档组织（通常为原发性结直肠癌）进行比较时，miR-31-3p评分相似。
我们的研究验证了miR-31-3p作为抗EGFR单克隆抗体潜在预测生物标志物的作用。
